Mei Hong Dr. med.
Advanced Glycated End Product Mediated Cell Activation Geboren am 08. 09. 1970 in Wuhan. V. R. China
Reifepruefung am 07. 1988 in Wuhan
Studiengang der Fachrichtung Medizin vom SS 1988 bis WS 1993 an der Universität Tongji in Wuhan
Magisterstudium vom SS 1994 bis WS 1997 an der Universität Tongji in Wuhan Staatsexamen im 08. 1999 an der Universität Tongji in Wuhan
Promotionsfach: Innere Medizin Doktorvater: Prof. Dr. med. R. Ziegler
Endothelin 1 (ET-1) which is released by endothelial cells is known to be one of the most potent vasoconstrictors and a mitogen to contribute to endothelial dysfunction.
Patients with poor glycemic control and diabetic nephropathy have shown to have elevated levels of AGEs and elevated levels of ET-1. Therefore, we investigated whether a link exists between hyperglycemia-dependent AGE formation and induction of ET-1. We induced ET-1 by incubation of BAECs with erythrocytes isolated from diabetic patients. Erythrocytes which derived from patients with poor glycemic control had a stronger ET-1-inducing activity on BAECs than erythrocytes derived from patients with good glycemic control. Western-blot assays confirm that erythrocyte lysate from hyperglycemic patients contained more CML-modified proteins than erythrocytes from subjects with good glycemic control. Binding AGE to RAGE results in the generation of intracellular oxidative stress and activation of the redox-sensitive NF-κB. Structural analysis of the ET-1 promoter revealed a putative NF-κB binding site between -2090 and -2081 bp. Consistently, this study indicates that CML-modified proteins not only increase ET-1 concentration but also increase the expression of ET-1 mRNA in BAECs. It seems that AGE-mediated ET-1 induction in endothelial cells is at least in part dependent on an oxidant-sensitive mechanism (data not shown). In AGE/RAGE-induced cells, RAGE appears to have a central role. A successful down regulation of ET-1 mRNA synthesis could be demonstrated after incubation with sRAGE. Furthermore, AGE/RAGE mediated NF- κB activation was also dependent on RAGE, since NF-κB activity was suppressed by blocking of RAGE with excess of sRAGE or antisense RAGE oligonucleotides. Thus, AGE mediates ET-1 induction and increased expression of ET-1 mRNA is dependent on RAGE.
